title: Alzheimer disease-related presenilin-1 variants exert distinct effects on monoamine oxidase-A activity in vitro.
abstract: Monoamine oxidase-A (MAO-A) has been associated with both depression and Alzheimer disease (AD). Recently, carriers of AD-related presenilin-1 (PS-1) alleles have been found to be at higher risk for developing clinical depression. We chose to examine whether PS-1 could influence MAO-A function in vitro. Overexpression of selected AD-related PS-1 variants (wildtype, Y115H, ΔEx9 and M146V) in mouse hippocampal HT-22 cells affects MAO-A catalytic activity in a variant-specific manner. The ability of the PS-1 substrate-competitor DAPT to induce MAO-A activity in cells expressing either PS-1 wildtype or PS-1(M146V) suggests the potential for a direct influence of PS-1 on MAO-A function. In support of this, we were able to co-immunoprecipitate MAO-A with FLAG-tagged PS-1 wildtype and M146V proteins. This potential for a direct protein-protein interaction between PS-1 and MAO-A is not specific for HT-22 cells as we were also able to co-immunoprecipitate MAO-A with FLAG-PS-1 variants in N2a mouse neuroblastoma cells and in HEK293 human embryonic kidney cells. Finally, we demonstrate that the two PS-1 variants reported to be associated with an increased incidence of clinical depression [e.g., A431E and L235V] both induce MAO-A activity in HT-22 cells. A direct influence of PS-1 variants on MAO-A function could provide an explanation for the changes in monoaminergic tone observed in several neurodegenerative processes including AD. The ability to induce MAO-A catalytic activity with a PS-1/γ-secretase inhibitor should also be considered when designing secretase inhibitor-based therapeutics.
authors.affiliation: Cell Signalling Laboratory, Department of Psychiatry, University of Saskatchewan, B45 HSB, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Pennington
authors.forename: Zelan
authors.initials: Z
authors.lastname: Wei
authors.forename: Lewei
authors.initials: L
authors.lastname: Rui
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doig
authors.forename: Brett
authors.initials: B
authors.lastname: Graham
authors.forename: Kelly
authors.initials: K
authors.lastname: Kuski
authors.forename: Geraldine G
authors.initials: GG
authors.lastname: Gabriel
authors.forename: Darrell D
authors.initials: DD
authors.lastname: Mousseau
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D003866:Depressive Disorder / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism*; D009447:Neuroblastoma / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D053764:Presenilin-1 / Q000235:genetics* / Q000502:physiology
chemical_list: D053764:Presenilin-1; D008995:Monoamine Oxidase